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1.  Association of Pulse Pressure, Arterial Elasticity, and Endothelial Function With Kidney Function Decline Among Adults With Estimated GFR > 60 mL/min/1.73 m2: The Multi-Ethnic Study of Atherosclerosis 
Background
The association of subclinical vascular disease and early declines in kidney function has not been well studied.
Study Design
Prospective cohort study
Setting & Participants
MESA participants with eGFR ≥60 ml/min/1.73m2 with follow-up of 5 years
Predictors
Pulse pressure (pulse pressure), small and large arterial elasticity (SAE, LAE), and flow mediated dilation.
Outcomes
kidney function decline
Measurements
SAE and LAE were measured by pulse contour analysis of the radial artery. Kidney function was measured by serum creatinine- and cystatin C-based eGFR.
Results
Among 4,853 adults, higher pulse pressure and lower SAE and LAE had independent and linear associations with faster rates of kidney function decline. Compared to persons with pulse pressure 40–50mmHg, eGFRSCysC decline was 0.29 (p=0.006), 0.56 (p<0.001), and 0.91 (p<0.001) ml/min/1.73m2/year faster among persons with pulse pressure 50–60, 60–70, and >70mmHg, respectively. Compared to the highest quartile of SAE (most elastic), eGFRSCysC decline was 0.26 (p=0.009), 0.35 (p=0.001), and 0.70 (p<0.001) ml/min/1.73m2/year faster for the second, third and fourth quartiles respectively. For LAE, compared to the highest quartile, eGFRSCysC decline was 0.28 (p=0.004), 0.58 (p<0.001), and 0.83 (p<0.001) ml/min/1.73m2/year faster for each decreasing quartile of LAE. Findings were similar with creatinine-based eGFR. In contrast, among 2,997 adults with flow-mediated dilation and kidney function measures, flow-mediated dilation was not significantly associated with kidney function decline. For every 1-SD greater flow-mediated dilation, eGFRSCysC and eGFRSCr changed by 0.05 ml/min/1.73m2/year (p=0.3) and 0.06 ml/min/1.73m2/year (p=0.04), respectively.
Limitations
We had no direct measure of GFR, in common with nearly all large population based studies.
Conclusions
Higher pulse pressure and lower arterial elasticity, but not flow-mediated dilation, were linearly and independently associated with faster kidney function decline among persons with eGFR ≥60 ml/min/1.73m2. Future studies investigate whether treatments to lower stiffness of large and small arteries may slow the rate of kidney function loss.
doi:10.1053/j.ajkd.2011.08.015
PMCID: PMC3242889  PMID: 22000727
kidney function; arterial elasticity; chronic kidney disease; atherosclerosis
2.  The Risk of Infection-Related Hospitalization With Decreased Kidney Function 
Background
Moderate kidney disease may predispose to infection. We sought to determine whether decreased kidney function, as estimated by serum cystatin C, was associated with the risk of infection-related hospitalization in older individuals.
Study Design
Cohort Study.
Setting & Participants
5,142 Cardiovascular Health Study participants with measured serum creatinine and cystatin C and without eGFR <15 ml/min/1.73 m2 at enrollment.
Predictor
The primary exposure of interest was estimated glomerular filtration rate using serum cystatin C (eGFRSCysC).
Outcome
Infection-related hospitalizations during a median follow-up of 11.5 years.
Results
In adjusted analyses, eGFRSCysC categories of 60–89, 45–59, and 15–44 ml/min/1.73 m2 were associated with 16%, 37%, and 64% greater risk of all-cause infection-related hospitalization, respectively, compared with an eGFRSCysC ≥90 ml/min/1.73 m2. When cause specific infection was examined, an eGFRSCysC of 15–44 ml/min/1.73 m2 was associated with an 80% greater risk of pulmonary and 160% greater risk of genitourinary infection compared with an eGFRSCysC ≥90 ml/min/1.73 m2.
Limitations
No measures of urinary protein, study limited to principal discharge diagnosis.
Conclusions
Lower kidney function, estimated using cystatin C, was associated with a linear and graded risk of infection-related hospitalization. These findings highlight that even moderate degrees of reduced kidney function are associated with clinically significant higher risks of serious infection in older individuals.
doi:10.1053/j.ajkd.2011.07.012
PMCID: PMC3288732  PMID: 21906862
renal disease; chronic kidney disease; infection; clinical epidemiology
3.  Combined Association of Albuminuria and Cystatin C–Based Estimated GFR With Mortality, Coronary Heart Disease, and Heart Failure Outcomes: The Atherosclerosis Risk in Communities (ARIC) Study 
Background
Serum cystatin C level has been shown to have a stronger association with clinical outcomes than serum creatinine level. However, little is known about the combined association of cystatin C–based estimated glomerular filtration rate (eGFRcys) and albuminuria with clinical outcomes, particularly at levels lower than current chronic kidney disease (CKD) cutoffs.
Study Design
Prospective cohort.
Setting & Participants
10,403 ARIC (Atherosclerosis Risk in Communities) Study participants followed up for a median of 10.2 years.
Predictor
eGFRcys, albuminuria.
Outcomes
Mortality, coronary heart disease (CHD), and heart failure, as well as a composite of any of these separate outcomes.
Results
Both decreased eGFRcys and albuminuria were associated independently with the composite outcome, as well as mortality, CHD, and heart failure. Although eGFRcys of 75-89 mL/min/1.73 m2 in the absence of albuminuria (albumin-creatinine ratio [ACR] <10 mg/g) or albuminuria with ACR of 10-29 mg/g with normal eGFRcys (90-104 mL/min/1.73 m2) was not associated significantly with any outcome compared with eGFRcys of 90-104 mL/min/1.73 m2 and ACR <10 mg/g, the risk of each outcome was significantly higher in those with both eGFRcys of 75-89 mL/min/1.73 m2 and ACR of 10-29 mg/g (for mortality, HR of 1.4 [95% CI, 1.1-2.0]; for CHD, HR of 1.9 [95% CI, 1.4-2.6]; for heart failure, HR of 1.8 [95% CI, 1.2-2.7]). Combining the 2 markers improved risk classification for all outcomes (P < 0.001), even in those without overt CKD.
Limitations
Only one measurement of cystatin C.
Conclusions
Mildly decreased eGFRcys and mild albuminuria independently contributed to the risk of mortality, CHD, and heart failure. Even minimally decreased eGFRcys (75-89 mL/min/1.73 m2) is associated with increased risk in the presence of mild albuminuria. Combining the 2 markers is useful for improved risk stratification even in those without clinical CKD.
doi:10.1053/j.ajkd.2012.03.011
PMCID: PMC3582350  PMID: 22537422
Epidemiology; kidney; outcomes
4.  Prevalence of kidney disease in anaemia differs by GFR-estimating method: The Third National Health and Nutrition Examination Survey (1988–94) 
Nephrology Dialysis Transplantation  2010;25(8):2542-2548.
Background. Anaemia worsens as kidney function declines. Both conditions are associated with increased mortality. Serum cystatin C is purportedly a more sensitive marker of kidney disease and a better predictor of mortality than serum creatinine. However, studies suggest that extrarenal factors also influence cystatin C levels.
Methods. We determined whether estimates of glomerular filtration rate [estimated glomerular filtration rate (eGFR)] based on serum cystatin C alone or in combination with serum creatinine were superior to those based on serum creatinine in recognizing impaired kidney function in the setting of anaemia in a sub-sample of the Third National Health and Nutrition Examination Survey of the USA consisting of 6734 participants, 20 years or older.
Results. The prevalence of moderate to severe kidney disease (eGFR 15–59 mL/min/1.73 m2) among anaemic persons was 15–16% when based on serum creatinine alone (eGFRSCR) or combined with cystatin C (eGFRSCR + CYSC); this estimate increased to nearly 25% when kidney function was estimated by cystatin C (eGFRCYSC). The adjusted odds ratios of kidney disease in anaemic versus non-anaemic persons were slightly higher with eGFRCYSC than eGFRSCR and eGFRSCR + CYSC in younger adults [odds ratio (OR) = 5.22, 95% confidence interval (CI): 2.23, 12.17], women (OR = 5.34, 95% CI: 2.36, 12.06) and those with elevated C-reactive protein (CRP) (OR = 7.36, 95% CI: 1.98–27.36).
Conclusions. Impaired kidney function was common in individuals with anaemia. Among anaemic individuals, the prevalence estimate for kidney disease was notably higher when kidney function was estimated by cystatin C alone compared with the estimations by serum creatinine alone or in combination with serum cystatin C. eGFRCYSC may be particularly helpful in identifying kidney disease in the setting of anaemia among younger persons, women and those with elevated CRP. Regardless of which renal biomarker is used, our study suggests that an evaluation for underlying kidney disease should be considered in the standard workup of anaemia.
doi:10.1093/ndt/gfq040
PMCID: PMC2910334  PMID: 20176612
anaemia; chronic kidney failure; creatinine; cystatin C; glomerular filtration rate
5.  Reduced Kidney Function and Preclinical Atherosclerosis in HIV-Infected Individuals: The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) 
American Journal of Nephrology  2011;33(5):453-460.
Background/Aims
Reduced kidney function and albuminuria are associated with higher risk for cardiovascular disease (CVD) and mortality in HIV-infected individuals. We investigated whether reduced estimated glomerular filtration rate (eGFR) and albuminuria are associated with subclinical vascular disease, as assessed by carotid intima-medial thickness (cIMT).
Methods
Cross-sectional analysis of 476 HIV-infected individuals without clinical evidence of CVD enrolled in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, using multivariable linear regression. eGFRCys and eGFRCr were calculated from cystatin C and creatinine levels. Albuminuria was defined as a positive urine dipstick (≥1+) or urine albumin-to-creatinine ratio ≥30 mg/g. Common and internal cIMT were measured by high-resolution B-mode ultrasound.
Results
In unadjusted analyses, eGFRCys and eGFRCr were strongly associated with common and internal cIMT. Each 10 ml/min/1.73 m2 decrease in eGFRCys and eGFRCr was associated with a 0.008 mm higher common cIMT (p = 0.003, p = 0.01) and a 0.024 and 0.029 mm higher internal cIMT (p = 0.003), respectively. These associations were eliminated after adjustment for age, gender, and race. Albuminuria showed little association with common or internal cIMT in all models.
Conclusions
In HIV-infected individuals without prior CVD, reduced kidney function and albuminuria were not independently associated with subclinical vascular disease, as assessed by cIMT. These results suggest that research should focus on searching for novel mechanisms by which kidney disease confers cardiovascular risk in HIV-infected individuals.
doi:10.1159/000327606
PMCID: PMC3100378  PMID: 21508633
Cystatin C; Intima-medial thickness; HIV; Atherosclerosis; Cardiovascular disease; Kidney
6.  Inflammation and Albuminuria in HIV-infected Patients Receiving Combination Antiretroviral Therapy 
Background:
The observed higher prevalence of albuminuria among HIV-infected patients has been strongly associated with cardiovascular disease and higher mortality. In HIV-seronegative patients with metabolic syndrome, malignancies and infections, pro-inflammatory cytokines, and acute phase reactants have been associated with albuminuria. However, the pathophysiology of albuminuria in HIV-seropositive individuals is poorly understood. We investigated the association of albuminuria with inflammatory biomarkers among HIV-infected patients on combination antiretroviral therapy.
Methods:
This is a cross-sectional analysis of the entry data of the participants enrolled in the Hawai‘i Aging with HIV-Cardiovascular Cohort. Participants were ≥ 40 years old, lived in Hawai‘i, documented HIV-positive, and had been on antiretroviral therapy for at least 6 months prior to recruitment. Albuminuria was defined as urine albumin-to-creatinine ratio (ACR) of 30 mg/g or higher, as assessed from single random urine collection. Microalbuminuria was defined as urine ACR between 30 and 300 mg/g and macroalbuminuria as urine ACR more than 300 mg/g. Plasma inflammatory biomarkers were assessed by multiplexing using Milliplex Human Cardiovascular Disease panels. Differences in clinical and laboratory characteristics between subjects with and without albuminuria were compared using a non-parametric Wilcoxon rank test for continuous variables and a chi-squared test for categorical variables. Univariate and multivariate logistic regression analyses were utilized to assess the association between presence of albuminuria as the dependent variable and plasma biomarkers as independent variables. Log-transformed plasma inflammatory biomarkers with P-value less than .1 in univariate logistic regression analysis were selected for examination in separate multivariate logistic regression models, adjusting for previously reported risk factors for albuminuria (age, gender, race, diabetes, hypertension, CD4 percent, current ritonavir, and tenofovir use).
Results:
Among a cohort of 111 HIV-infected patients (median age of 52 (Q1: 46, Q3: 57); male 86%; diabetes 6%; hypertension 33%; median CD4 count of 489 cells/mm3(Q1:341, Q3: 638); HIV RNA PCR < 48 copies/ml 85%), eighteen subjects (16.2%) had microalbuminuria, and two subjects (1.8%) had macroalbuminuria. There was no significant difference in CD4 count and HIV viral loads between patients with and without albuminuria. In univariate logistic regression analysis, higher levels of log-transformed soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule 1 (sVCAM-1), tissue plasminogen activator inhibitor-1 (tPAI-1), C-reactive protein (CRP), serum amyloid A (SAA), serum amyloid P (SAP), interleukin-1β, interleukin-8, and tumor necrosis factor-α (TNF-α) were associated with albuminuria (P < .10). In multivariate logistic regression models, sE-selectin, sVCAM-1, tPAI-1, CRP, and SAP remained significant (P < .05) even after adjustment for previously reported risk factors for albuminuria.
Conclusions:
This study has shown an association between inflammation and albuminuria independent of previously reported risk factors for albuminuria in HIV-infected subjects on stable combination antiretroviral therapy. Chronic low-grade inflammation despite potent antiretroviral treatment may be one of the factors causing higher rates of albuminuria among HIV-infected patients. Future studies are needed to further elucidate the pathophysiologic mechanisms of chronic inflammation in HIV and its impact on kidney disease.
PMCID: PMC4175929
7.  Cystatin C, Albuminuria, and Mortality Among Older Adults With Diabetes 
Diabetes Care  2009;32(10):1833-1838.
OBJECTIVE
Albuminuria and impaired glomerular filtration rate (GFR) are each associated with poor health outcomes among individuals with diabetes. Joint associations of albuminuria and impaired GFR with mortality have not been comprehensively evaluated in this population.
RESEARCH DESIGN AND METHODS
This is a cohort study among Cardiovascular Health Study participants with diabetes, mean age 78 years. GFR was estimated using serum cystatin C and serum creatinine. Albumin-to-creatinine ratio (ACR) was measured in single-voided urine samples.
RESULTS
Of 691 participants, 378 died over 10 years of follow-up. Cystatin C–estimated GFR <60 ml/min per 1.73 m2, creatinine-based estimated GFR <60 ml/min per 1.73 m2, and urine ACR ≥30 mg/g were each associated with increased mortality risk with hazard ratios of 1.73 (95% CI 1.37–2.18), 1.54 (1.21–1.97), and 1.73 (1.39–2.17), respectively, adjusting for age, sex, race, diabetes duration, hypoglycemic medications, hypertension, BMI, smoking, cholesterol, lipid-lowering medications, prevalent cardiovascular disease (CVD), and prevalent heart failure. Cystatin C–estimated GFR and urine ACR were additive in terms of mortality risk. Cystatin C–estimated GFR predicted mortality more strongly than creatinine-based estimated GFR.
CONCLUSIONS
Albuminuria and impaired GFR were independent, additive risk factors for mortality among older adults with diabetes. These findings support current recommendations to regularly assess both albuminuria and GFR in the clinical care of patients with diabetes; a focus on interventions to prevent or treat CVD in the presence of albuminuria, impaired GFR, or both; and further consideration of cystatin C use in clinical care.
doi:10.2337/dc09-0191
PMCID: PMC2752913  PMID: 19587367
8.  Association between First Nations ethnicity and progression to kidney failure by presence and severity of albuminuria 
Background:
Despite a low prevalence of chronic kidney disease (estimated glomerular filtration rate [GFR] < 60 mL/min per 1.73 m2), First Nations people have high rates of kidney failure requiring chronic dialysis or kidney transplantation. We sought to examine whether the presence and severity of albuminuria contributes to the progression of chronic kidney disease to kidney failure among First Nations people.
Methods:
We identified all adult residents of Alberta (age ≥ 18 yr) for whom an outpatient serum creatinine measurement was available from May 1, 2002, to Mar. 31, 2008. We determined albuminuria using urine dipsticks and categorized results as normal (i.e., no albuminuria), mild, heavy or unmeasured. Our primary outcome was progression to kidney failure (defined as the need for chronic dialysis or kidney transplantation, or a sustained doubling of serum creatinine levels). We calculated rates of progression to kidney failure by First Nations status, by estimated GFR and by albuminuria category. We determined the relative hazard of progression to kidney failure for First Nations compared with non–First Nations participants by level of albuminuria and estimated GFR.
Results:
Of the 1 816 824 participants we identified, 48 669 (2.7%) were First Nations. First Nations people were less likely to have normal albuminuria compared with non–First Nations people (38.7% v. 56.4%). Rates of progression to kidney failure were consistently 2- to 3-fold higher among First Nations people than among non–First Nations people, across all levels of albuminuria and estimated GFRs. Compared with non–First Nations people, First Nations people with an estimated GFR of 15.0–29.9 mL/min per 1.73 m2 had the highest risk of progression to kidney failure, with similar hazard ratios for those with normal and heavy albuminuria.
Interpretation:
Albuminuria confers a similar risk of progression to kidney failure for First Nations and non–First Nations people.
doi:10.1503/cmaj.130776
PMCID: PMC3903763  PMID: 24295865
9.  Chronic kidney disease and estimates of kidney function in HIV infection: a cross-sectional study in the Multicenter AIDS Cohort Study 
Background
Cystatin C has been proposed as an alternative marker of kidney function among HIV-infected persons in whom serum creatinine is affected by extra-renal factors.
Methods
In this cross-sectional study, we compared estimated glomerular filtration rates (eGFR) using serum creatinine versus cystatin C between 150 HIV-uninfected and 783 HIV-infected men. We evaluated the prevalence of chronic kidney disease (CKD; eGFR<60 mL/min/1.73 m2) and examined the influence of extra-renal factors on GFR-estimates among HIV-infected men.
Results
Estimated GFRSCR was similar by HIV serostatus, but eGFRCYSC was lower in HIV-infected men. A higher proportion of HIV-infected men were classified as having CKD when using eGFRCYSC versus eGFRSCR (7% vs. 5%, P<0.01). In HIV-infected individuals without CKD, eGFRSCR was higher than eGFRCYSC while it was lower than eGFRCYSC in persons with CKD. In HIV-infected men, older age, proteinuria, and prior clinical AIDS were inversely associated with both GFR-estimates. Higher serum albumin levels and ACE-inhibitor/ARB use were associated with lower eGFRSCR. HIV viral load, hepatitis C co-infection, and serum alkaline phosphatase were inversely associated with eGFRCYSC.
Conclusion
Among HIV-uninfected and HIV-infected men of similar social risk behaviors, GFR estimates differed by biomarker and kidney function level. Estimated GFRCYSC classified a larger proportion of HIV-infected men with CKD compared to eGFRSCR. Differences between these GFR-estimating methods may be due to the effects of extra-renal factors on serum creatinine and cystatin C. Until GFR-estimating equations are validated among HIV-infected individuals, current GFR estimates based on these biomarkers should be interpreted with care in this patient population.
doi:10.1097/QAI.0b013e318222f461
PMCID: PMC3159728  PMID: 21646913
HIV; kidney disease; serum creatinine; cystatin C; glomerular filtration rate; Multicenter AIDS Cohort Study
10.  Cystatin C Level as a Marker of Kidney Function in Human Immunodeficiency Virus Infection 
Archives of internal medicine  2007;167(20):2213-2219.
Background
Although studies have reported a high prevalence of end-stage renal disease in human immunodeficiency virus (HIV)-infected individuals, little is known about moderate impairments in kidney function. Cystatin C measurement may be more sensitive than creatinine for detecting impaired kidney function in persons with HIV.
Methods
We evaluated kidney function in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort, a representative sample of 1008 HIV-infected persons and 290 controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study in the United States.
Results
Cystatin C level was elevated in HIV-infected individuals; the mean±SD cystatin C level was 0.92±0.22 mg/L in those infected with HIV and 0.76±0.15 mg/L in controls (P<.001). In contrast, both mean creatinine levels and estimated glomerular filtration rates appeared similar in HIV-infected individuals and controls (0.87±0.21 vs 0.85±0.19 mg/dL [to convert to micromoles per liter, multiply by 88.4] [P=.35] and 110±26 vs 106±23 mL/min/1.73 m2 [P=.06], respectively). Persons with HIV infection were more likely to have a cystatin C level greater than 1.0 mg/L (OR, 9.8; 95% confidence interval, 4.4-22.0 [P<.001]), a threshold demonstrated to be associated with increased risk for death and cardiovascular and kidney disease. Among participants with HIV, potentially modifiable risk factors for kidney disease, hypertension, and low high-density lipoprotein concentration were associated with a higher cystatin C level, as were lower CD4 lymphocyte count and coinfection with hepatitis C virus (all P<.001).
Conclusions
Individuals infected with HIV had substantially worse kidney function when measured by cystatin Clevel compared with HIV-negative controls, whereas mean creatinine levels and estimated glomerular filtration rates were similar. Cystatin C measurement could be a useful clinical tool to identify HIV-infected persons at increased risk for kidney and cardiovascular disease.
doi:10.1001/archinte.167.20.2213
PMCID: PMC3189482  PMID: 17998494
11.  The Association Between Kidney Function and Albuminuria with Cardiovascular Events in HIV-Infected Persons 
Circulation  2010;121(5):651-658.
Background
Cardiovascular disease (CVD) is now a leading cause of death in HIV-infected persons; however, risk markers for CVD are ill-defined in this population. We examined the association between longitudinal measures of kidney function and albuminuria with risk of atherosclerotic CVD and heart failure in a contemporary cohort of HIV-infected individuals.
Methods and Results
We followed a national sample of 17,264 HIV-infected persons receiving care in the Veterans Health Administration for: (1) incident CVD, defined as coronary, cerebrovascular, or peripheral arterial disease; and (2) incident heart failure. Rates of CVD and heart failure were at least 6-fold greater in the highest risk patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 and albuminuria ≥300 mg/dL versus those with no evidence of kidney disease (eGFR ≥60 mL/min/1.73m2 and no albuminuria). After multivariable adjustment, eGFR levels 45–59, 30–44, and <30 mL/min/1.73m2 were associated with hazard ratios (HR) for incident CVD of 1.46 (95% confidence interval 1.15–1.86), 2.03 (1.47–2.82), and 1.99 (1.46–2.70), compared with eGFR ≥60 mL/min/1.73m2. Similarly, albuminuria levels 30, 100, and ≥300 mg/dL had HR’s for CVD of 1.28 (1.09–1.51), 1.48 (1.15–1.90), and 1.71 (1.30–2.27), compared with absent albuminuria. The associations between eGFR and albuminuria with heart failure were larger in magnitude and followed the same trends.
Conclusion
In this national sample of HIV-infected persons, eGFR and albuminuria levels were strongly associated with risk of CVD and heart failure. Kidney function and albuminuria provide complementary prognostic information which may aid CVD risk stratification in HIV-infected persons.
doi:10.1161/CIRCULATIONAHA.109.898585
PMCID: PMC2829672  PMID: 20100969
HIV; albuminuria; glomerular filtration rate; heart failure; cardiovascular disease
12.  Detection of Chronic Kidney Disease With Creatinine, Cystatin C, and Urine Albumin-to-Creatinine Ratio and Association With Progression to End-Stage Renal Disease and Mortality 
Context
A triple-marker approach for chronic kidney disease (CKD) evaluation has not been well studied.
Objective
To evaluate whether combining creatinine, cystatin C, and urine albumin-to-creatinine ratio (ACR) would improve identification of risks associated with CKD compared with creatinine alone.
Design, Setting, and Participants
Prospective cohort study involving 26 643 US adults enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from January 2003 to June 2010. Participants were categorized into 8 groups defined by estimated glomerular filtration rate (GFR) determined by creatinine and by cystatin C of either <60 or ≥60 mL/min/1.73 m2 and ACR of either <30 or ≥30 mg/g.
Main Outcome Measures
All-cause mortality and incident end-stage renal disease with median follow-up of 4.6 years.
Results
Participants had a mean age of 65 years, 40% were black, and 54% were women. Of 26 643 participants, 1940 died and 177 developed end-stage renal disease. Among participants without CKD defined by creatinine, 24% did not have CKD by either ACR or cystatin C. Compared with those with CKD defined by creatinine alone, the hazard ratio for death in multivariable-adjusted models was 3.3 (95% confidence interval [CI], 2.0–5.6) for participants with CKD defined by creatinine and ACR; 3.2 (95% CI, 2.2–4.7) for those with CKD defined by creatinine and cystatin C, and 5.6 (95% CI, 3.9–8.2) for those with CKD defined by all biomarkers. Among participants without CKD defined by creatinine, 3863 (16%) had CKD detected by ACR or cystatin C. Compared with participants who did not have CKD by any measure, the HRs for mortality were 1.7 (95% CI, 1.4–1.9) for participants with CKD defined by ACR alone, 2.2 (95% CI, 1.9–2.7) for participants with CKD defined by cystatin C alone, and 3.0 (95% CI, 2.4–3.7) for participants with CKD defined by both measures. Risk of incident end-stage renal disease was higher among those with CKD defined by all markers (34.1 per 1000 person-years; 95% CI, 28.7–40.5 vs 0.33 per 1000 person-years; 95% CI, 0.05–2.3) for those with CKD defined by creatinine alone. The second highest end-stage renal disease rate was among persons missed by the creatinine measure but detected by both ACR and cystatin C (rate per 1000 person-years, 6.4; 95% CI, 3.6–11.3). Net reclassification improvement for death was 13.3% (P<.001) and for end-stage renal disease was 6.4% (P<.001) after adding estimated GFR cystatin C in fully adjusted models with estimated GFR creatinine and ACR.
Conclusion
Adding cystatin C to the combination of creatinine and ACR measures improved the predictive accuracy for all-cause mortality and end-stage renal disease.
doi:10.1001/jama.2011.468
PMCID: PMC3697771  PMID: 21482744
13.  Inflammation, kidney function and albuminuria in the Framingham Offspring cohort 
Background. Inflammation and chronic kidney disease (CKD) are both associated with cardiovascular disease (CVD). Whether inflammatory biomarkers are associated with kidney function and albuminuria after accounting for traditional CVD risk factors is not completely understood.
Methods. The sample comprised Framingham Offspring cohort participants (n = 3294, mean age 61, 53% women) who attended the seventh examination cycle (1998–2001). Inflammatory biomarkers [C-reactive protein (CRP), tumour necrosis factor (TNF)-alpha, interleukin-6, TNF receptor 2 (TNFR2), intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), P-selectin, CD-40 ligand, osteoprotegerin, urinary isoprostanes, myeloperoxidase and fibrinogen] were measured on fasting blood samples. Serum creatinine-based estimated glomerular filtration rate (eGFR) and serum cystatin C concentration were used to assess kidney function. Urinary albumin-to-creatinine ratio (UACR) was used to assess albuminuria. Linear or logistic regression was used to test associations between biomarkers and kidney measures.
Results. Chronic kidney disease (CKD), defined as eGFR < 59/64 mL/min/1.73 m2 in women/men, was present in 8.8% (n = 291) of participants. TNF-alpha, interleukin-6, TNFR2, MCP-1, osteoprotegerin, myeloperoxidase and fibrinogen were higher among individuals with CKD; all biomarkers except for urinary isoprostanes were elevated in higher cystatin C quartiles; and TNF-alpha, interleukin-6, TNFR2, ICAM-1 and osteoprotegerin were elevated in higher UACR quartiles—all assessed after multivariable adjustment. Almost 6% and 17% of variability in TNFR2 were explained by CKD status and higher cystatin C quartiles, respectively.
Conclusions. Biomarkers of inflammation are associated with kidney function and albuminuria. In particular, substantial variability in soluble TNFR2 is explained by CKD and cystatin C.
doi:10.1093/ndt/gfq471
PMCID: PMC3108344  PMID: 20682604
albuminuria; chronic kidney disease; C-reactive protein; inflammation
14.  Prevalence and Determinants of Diabetic Nephropathy in Korea: Korea National Health and Nutrition Examination Survey 
Diabetes & Metabolism Journal  2014;38(2):109-119.
Background
Diabetic nephropathy is a leading cause of end stage renal disease and is associated with an increased risk of cardiovascular mortality. It manifests as albuminuria or impaired glomerular filtration rate (GFR), and the prevalence of diabetic nephropathy varies with ethnicity. The prevalence of diabetic nephropathy and its determinants in Korean adults have not previously been studied at the national level. This cross-sectional study was undertaken to ascertain the prevalence and determinants of albuminuria and chronic kidney disease (CKD) in Korean patients with diabetes.
Methods
The Korea National Health and Nutrition Examination Survey (KNHANES) V, conducted in 2011, was used to define albuminuria (n=4,652), and the dataset of KNHANES IV-V (2008-2011) was used to define CKD (n=21,521). Selected samples were weighted to represent the entire civilian population in Korea. Albuminuria was defined as a spot urine albumin/creatinine ratio >30 mg/g. CKD was defined as a GFR <60 mL/min/1.73 m2.
Results
Among subjects with diabetes, 26.7% had albuminuria, and 8.6% had CKD. Diabetes was associated with an approximate 2.5-fold increased risk of albuminuria, with virtually no difference between new-onset and previously diagnosed diabetes. Only systolic blood pressure was significantly associated with albuminuria, and old age, high serum triglyceride levels, and previous cardiovascular disease (CVD) were related with CKD in subjects with diabetes.
Conclusion
Korean subjects with diabetes had a higher prevalence of albuminuria and CKD than those without diabetes. Blood pressure was associated with albuminuria, and age, triglyceride level, and previous CVD were independent determinants of CKD in subjects with diabetes.
doi:10.4093/dmj.2014.38.2.109
PMCID: PMC4021298  PMID: 24851205
Albuminuria; Chronic renal disease; Diabetes mellitus; Diabetic nephropathy; Korea
15.  Albuminuria, impaired kidney function and cardiovascular outcomes or mortality in the elderly 
Nephrology Dialysis Transplantation  2009;25(5):1560-1567.
Background. Kidney disease is a risk factor for mortality and cardiovascular disease in older adults, but the separate and combined effects of albuminuria and cystatin C, a novel marker of glomerular filtration, are not known.
Methods. We examined associations of these markers with mortality and cardiovascular outcomes during a median follow-up of 8.3 years in 3291 older adults in the Cardiovascular Health Study. Kidney disease was assessed using urinary albumin/creatinine ratio (ACR), cystatin C and Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR). We defined subgroups based on presence of microalbuminuria (MA, ACR > 30 mg/g) and categories of normal kidney function (cystatin C < 1.0 mg/L and eGFR > 60 mL/min/1.73 m2); preclinical kidney disease (cystatin C level > 1.0 mg/l but eGFR > 60 mL/min/1.73 m2); and chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m2). Cox proportional hazards models were used to examine associations between these six subgroups and all-cause or cardiovascular mortality, myocardial infarction and heart failure.
Results. One thousand one hundred fifty (34.9%) had normal kidney function (12.2% with MA), 1518 (46.1%) had preclinical kidney disease (17.9% with MA) and 622 (18.9%) had CKD (47% with MA). After adjustment, the presence of either preclinical kidney disease or MA was associated with an over 50% increase in mortality risk; the presence of both was associated with a 2.4-fold mortality risk. Those with CKD and MA were at highest risk, with a nearly 4-fold mortality risk.
Conclusion. Elevated cystatin C and albuminuria are common, identify different subsets of the older population, and are independent, graded risk factors for cardiovascular disease and mortality.
doi:10.1093/ndt/gfp646
PMCID: PMC3307251  PMID: 20008829
albuminuria; aging; cardiovascular diseases; kidney function; mortality
16.  Associations of Urinary Levels of Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-Associated Lipocalin (NGAL) With Kidney Function Decline in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Whether elevations of urinary biomarkers of tubular injury (urine neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1)) are associated with future risk of kidney disease has not been investigated.
Study Design
1:1 nested case-control study
Setting & Participants
686 participants in the Multi-Ethnic Study of Atherosclerosis (MESA).
Predictor
NGAL and KIM-1 were measured at baseline and expressed as log-transformed continuous variables and categorized into deciles.
Outcomes
Kidney function was estimated by cystatin C using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Incident CKD Stage 3 was defined as eGFR <60 ml/min/1.73m2 and a eGFR decline >1 ml/min/1.73m2 per year, and rapid kidney function decline (RKFD) was defined as decline of ≥3 ml/min/1.73m2 per year.
Measurements
Cases were defined as persons with eGFR >60 ml/min/1.73m2 who subsequently developed incident CKD Stage 3 and/or had RKFD by MESA year 5 visit. Controls were matched for age, gender, race, diabetes, and baseline eGFR. We adjusted for age, hypertension and presence of albuminuria (ACR ≥30 mg/g).
Results
Of the 343 cases, 145 had incident CKD Stage 3, 141 had RKFD and 57 had both. Mean eGFR for controls was 81 (±10) ml/min/1.73m2 at baseline and 80 (±10) at follow-up, compared with 82 (±13) and 58 (±10) for cases. Each doubling of KIM-1 (pg/ml) was associated with an OR of 1.15 (95% CI, 1.02-1.29) for incident CKD Stage 3 and/or RKFD. Compared to the lowest 90%, the highest decile of KIM-1 was associated with an OR of 2.02 (95% CI, 1.15-3.56) for the outcome; these associations were independent of albuminuria. NGAL levels (ng/ml) were not associated with incident CKD Stage 3 and/or RKFD (OR, 1.04; 95% CI, 0.99-1.10). Results were similar when KIM-1 and NGAL were standardized for urine creatinine.
Limitations
The case-control design limits ability to account for persons who died or were not available for follow-up.
Conclusions
Urinary KIM-1 is associated with future risk of kidney disease independent of albuminuria. Urinary biomarkers of tubular injury are a promising tool for identifying persons at risk for CKD.
doi:10.1053/j.ajkd.2012.05.014
PMCID: PMC3690926  PMID: 22749388
KIM-1; NGAL; kidney function decline
17.  Urinary Markers of Kidney Injury and Kidney Function Decline in HIV-Infected Women 
Objective
HIV-infected persons have substantially higher risk of kidney failure than persons without HIV, but serum creatinine levels are insensitive for detecting declining kidney function. We hypothesized that urine markers of kidney injury would be associated with declining kidney function among HIV-infected women.
Methods
In the Women's Interagency HIV Study (WIHS), we measured concentrations of albumin-to-creatinine ratio (ACR), interleukin-18 (IL-18), kidney injury marker-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) from stored urine among 908 HIV-infected and 289 uninfected participants. Primary analyses used cystatin C based estimated glomerular filtration rate (CKD-EPI eGFRcys) as the outcome, measured at baseline and two follow-up visits over eight years; secondary analyses used creatinine (CKD-EPI eGFRcr). Each urine biomarker was categorized into tertiles, and kidney decline was modeled with both continuous and dichotomized outcomes.
Results
Compared with the lowest tertiles, the highest tertiles of ACR (−0.15ml/min/1.73m2, p<0.0001), IL-18 (−0.09ml/min/1.73m2, p<0.0001) and KIM-1 (−0.06ml/min/1.73m2, p<0.001) were independently associated with faster eGFRcys decline after multivariate adjustment including all three biomarkers among HIV-infected women. Among these biomarkers, only IL-18 was associated with each dichotomized eGFRcys outcome: ≥3% (Relative Risk 1.40; 95%CI 1.04-1.89); ≥5% (1.88; 1.30-2.71); and ≥10% (2.16; 1.20-3.88) for the highest versus lowest tertile. In alternative models using eGFRcr, the high tertile of KIM-1 had independent associations with 5% (1.71; 1.25-2.33) and 10% (1.78; 1.07-2.96) decline, and the high IL-18 tertile with 10% decline (1.97; 1.00-3.87).
Conclusions
Among HIV-infected women in the WIHS cohort, novel urine markers of kidney injury detect risk for subsequent declines in kidney function.
doi:10.1097/QAI.0b013e3182737706
PMCID: PMC3509242  PMID: 23023103
HIV; KIM-1; NGAL; IL-18; albumin-to-creatinine ratio; cystatin C; kidney injury
18.  Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in Intensive Care: Extended Follow-up of a Randomized Controlled Trial 
PLoS Medicine  2014;11(2):e1001601.
Martin Gallagher and colleagues examine the long-term outcomes of renal replacement therapy (RRT) dosing in patients with acute kidney injury randomized to normal vs. augmented RRT.
Please see later in the article for the Editors' Summary
Background
The incidence of acute kidney injury (AKI) is increasing globally and it is much more common than end-stage kidney disease. AKI is associated with high mortality and cost of hospitalisation. Studies of treatments to reduce this high mortality have used differing renal replacement therapy (RRT) modalities and have not shown improvement in the short term. The reported long-term outcomes of AKI are variable and the effect of differing RRT modalities upon them is not clear. We used the prolonged follow-up of a large clinical trial to prospectively examine the long-term outcomes and effect of RRT dosing in patients with AKI.
Methods and Findings
We extended the follow-up of participants in the Randomised Evaluation of Normal vs. Augmented Levels of RRT (RENAL) study from 90 days to 4 years after randomization. Primary and secondary outcomes were mortality and requirement for maintenance dialysis, respectively, assessed in 1,464 (97%) patients at a median of 43.9 months (interquartile range [IQR] 30.0–48.6 months) post randomization. A total of 468/743 (63%) and 444/721 (62%) patients died in the lower and higher intensity groups, respectively (risk ratio [RR] 1.04, 95% CI 0.96–1.12, p = 0.49). Amongst survivors to day 90, 21 of 411 (5.1%) and 23 of 399 (5.8%) in the respective groups were treated with maintenance dialysis (RR 1.12, 95% CI 0.63–2.00, p = 0.69). The prevalence of albuminuria among survivors was 40% and 44%, respectively (p = 0.48). Quality of life was not different between the two treatment groups. The generalizability of these findings to other populations with AKI requires further exploration.
Conclusions
Patients with AKI requiring RRT in intensive care have high long-term mortality but few require maintenance dialysis. Long-term survivors have a heavy burden of proteinuria. Increased intensity of RRT does not reduce mortality or subsequent treatment with dialysis.
Trial registration
www.ClinicalTrials.gov NCT00221013
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. Chronic kidney disease (caused, for example, by diabetes) gradually destroys the kidneys' filtration units (the nephrons), eventually leading to life-threatening end-stage kidney disease. However, the kidneys can also stop working suddenly because of injury, infection, or poisoning. Acute kidney injury (AKI) is much more common than end-stage kidney disease and its incidence is increasing worldwide. In the US, for example, the number of hospitalizations that included an AKI diagnosis rose from 4,000 in 1996 to 23,000 in 2008. Moreover, nearly half of patients with AKI will die shortly after the condition develops. Symptoms of AKI include changes in urination, swollen feet and ankles, and tiredness. Treatments for AKI aim to prevent fluid and waste build up in the body and treat the underlying cause (e.g., severe infection or dehydration) while allowing the kidneys time to recover. In some patients, it is sufficient to limit the fluid intake and to reduce waste build-up by eating a diet that is low in protein, salt, and potassium. Other patients need renal replacement therapy (RRT), life-supporting treatments such as hemodialysis and hemofiltration, two processes that clean the blood by filtering it outside the body.
Why Was This Study Done?
The long-term outcomes of AKI (specifically, death and chronic kidney disease) and the effects of different RRT modalities on these outcomes are unclear. A recent controlled trial that randomly assigned patients with AKI who were managed in intensive care units (ICUs) to receive two different intensities of continuous hemodiafiltration (a combination of hemodialysis and hemofiltration) found no difference in all-cause mortality (death) at 90 days. Here, the researchers extend the follow-up of this trial (the Randomized Evaluation of Normal vs. Augmented Levels of renal replacement therapy [RENAL] study) to investigate longer-term mortality, the variables that predict mortality, treatment with long-term dialysis (an indicator of chronic kidney disease), and functional outcomes in patients with AKI treated with different intensities of continuous RRT.
What Did the Researchers Do and Find?
For the Prolonged Outcomes Study of RENAL (POST-RENAL), the researchers extended the follow-up of the RENAL participants up to 4 years. Over an average follow-up of 43.9 months, 63% of patients in the lower intensity treatment group died compared to 62% of patients in the higher intensity group. Overall, a third of patients who survived to 90 days died during the extended follow-up. Among the survivors to day 90, 5.1% and 5.8% of patients in the lower and higher intensity groups, respectively, were treated with maintenance dialysis during the extended follow-up. Among survivors who consented to analysis, 40% and 44% of patients in the lower and higher intensity groups, respectively, had albuminuria (protein in the urine, an indicator of kidney damage). Patients in both groups had a similar quality life (determined through telephone interviews). Finally, increasing age, APACHE III score (a scoring system that predicts the survival of patients in ICU), and serum creatinine level (an indicator of kidney function) at randomization were all predictors of long-term mortality.
What Do These Findings Mean?
These findings indicate that patients with AKI in ICUs who require RRT have a high long-term mortality. They show that few survivors require maintenance dialysis for chronic kidney disease but that there is a substantial rate of albuminuria among survivors despite relative preservation of kidney function. The findings also suggest that the intensity of RRT has no significant effect on mortality or the need for dialysis. Because these findings were obtained in a randomized controlled trial, they may not be generalizable to other patient populations. Moreover, although data on mortality and maintenance dialysis were available for all the trial participants, clinical and biochemical outcomes were only available for some participants and may not be representative of all the participants. Despite these study limitations, these findings suggest that survivors of AKI may be at a high risk of death or of developing chronic kidney disease. Survivors of AKI are, therefore, at high risk of further illness and long-term albuminuria reduction strategies may offer a therapeutic intervention for this group of patients.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001601.
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about the kidneys and about all aspects of kidney disease and its treatment; the US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The Mayo Clinic provides information for patients about acute kidney injury
Wikipedia has a page on acute kidney injury (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers, including a link to a video about acute kidney injury
World Kidney Day, a joint initiative between the International Society of Nephrology and the International Federation of Kidney Foundations (IFKF), aims to raise awareness about kidneys and kidney disease; its website provides information about acute kidney injury
The MedlinePlus Encyclopedia has a pages about acute kidney failure and about renal dialysis
The UK National Institute for Health and Care Excellence (NICE) recently published new guidelines on the treatment of acute kidney injury; a clinical practice guideline for acute kidney injury produced by KDIGO (a not-for-profit organization that aims to improve the care and outcomes of kidney disease patients worldwide through the development and implementation of global clinical practice guidelines) is available; the Acute Kidney Injury app provides a fast and simple way to explore guidelines on the diagnosis, prevention, and management of AKI
doi:10.1371/journal.pmed.1001601
PMCID: PMC3921111  PMID: 24523666
19.  Comparison of Measured GFR, Serum Creatinine, Cystatin C, and Beta-Trace Protein to Predict ESRD in African Americans With Hypertensive CKD 
Background
Identification of persons with chronic kidney disease (CKD) who are at highest risk to progress to end stage renal disease (ESRD) is necessary to reduce the burden of kidney failure. The relative utility of traditional markers of kidney function, including estimated glomerular filtration rate (GFR) and serum creatinine, and emerging markers of kidney function, including cystatin C and beta-trace protein (BTP), to predict ESRD and mortality has yet to be established.
Study Design
Randomized clinical trial followed by an observational cohort study.
Setting & Participants
865 African American individuals with hypertensive CKD enrolled in a clinical trial of two levels of blood pressure control and three different antihypertensive drugs as initial therapy and subsequently followed by an observational cohort study.
Predictors
Quintile of measured GFR (mGFR) by iothalamate clearance, serum creatinine, serum creatinine-based estimated GFR (eGFRSCr), cystatin C, and BTP.
Outcomes and Measurements
Incidence of ESRD and mortality.
Results
A total of 246 participants reached ESRD over a median follow-up of 102 months. The incidence rate of ESRD was higher with higher quintiles of each marker. The association between higher BTP and ESRD was stronger than those for the other markers, including mGFR. All the markers remained significantly associated with ESRD after adjustment for mGFR and relevant covariates (all p<0.05), with BTP retaining the strongest association (HR for highest versus lowest quintile, 5.7; 95% CI, 2.2-14.9). Associations with the combined endpoint of ESRD or mortality (n=390) were weaker, but remained significant for cystatin C (p=0.05) and BTP (p=0.004).
Limitations
The ability of these markers to predict ESRD and mortality in other racial and ethnic groups and among individuals with CKD due to other causes is unknown.
Conclusions
Plasma BTP and cystatin C may be useful adjuncts to serum creatinine and mGFR in evaluating risk for progression of kidney disease.
doi:10.1053/j.ajkd.2011.07.018
PMCID: PMC3221777  PMID: 21944667
End-stage renal disease; beta trace protein; cystatin C; serum creatinine; iothalamate glomerular filtration rate
20.  Predictors of Incident Albuminuria in the Framingham Offspring Cohort 
Background
Predictors for incident albuminuria are not well-known in population based cohorts. The purpose of this study was to identify predictors of incident albuminuria in an unselected, middle-aged population.
Study Design
Observational cohort study
Setting and participants
Framingham Offspring Study participants who attended both the sixth (baseline; 1995–1998) and eighth (2005–2008) examination cycles.
Predictors
Standard clinical predictors were used. Predictors of incident albuminuria were identified by stepwise logistic regression analysis with age and sex forced into the model.
Outcomes and Measurements
Albuminuria was defined as urine albumin-creatinine ratio (UACR) ≥17 mg/g (men) or ≥ 25 mg/g (women). Individuals with albuminuria at baseline were excluded.
Results
1916 participants were available for analysis (mean age 56 years, 54% women). Albuminuria developed in 10.0% of participants (n=192) over 9.5 years. Age (odds ratio [OR], 2.09; p-value<0.001), baseline diabetes (OR, 1.93; p-value= 0.01), smoking (OR, 2.09; p-value <0.001) and baseline log UACR (OR per standard deviation increase in log UACR, 1.56; p-value <0.001) were associated with incident albuminuria in a stepwise model. An inverse relationship with female sex (OR, 0.53; p <0.001) and HDL cholesterol (OR, 0.80; p-value=0.007) was also observed. Results were similar when participants with baseline chronic kidney disease (n=102), defined as eGFR < 60 mL/min/1.73 m2, were excluded from the model. Age, male sex, low HDL-cholesterol, smoking and log UACR continued to be associated with incident albuminuria when baseline diabetes (n= 107) was excluded. Age, male sex and log UACR correlated with incident albuminuria after participants with baseline hypertension were excluded (n= 651).
Limitations
Causality may not be inferred due to the observational nature of the study. One-third of participants did not return for follow-up, potentially attenuating the observed risks for albuminuria.
Conclusions
The known cardiovascular risk factors of increasing age, male sex, diabetes, smoking, low HDL cholesterol, and albuminuria within the “normal range” are correlates of incident albuminuria in the general population.
doi:10.1053/j.ajkd.2010.04.013
PMCID: PMC3198053  PMID: 20599306
Microalbuminuria; albuminuria; proteinuria
21.  Cystatin C as an Early Biomarker of Nephropathy in Patients with Type 2 Diabetes 
Journal of Korean Medical Science  2011;26(2):258-263.
This study was done to evaluate clinical usefulness of cystatin C levels of serum and urine in predicting renal impairment in normoalbuminuric patients with type 2 diabetes and to evaluate the association between albuminuria and serum/urine cystatin C. Type 2 diabetic patients (n = 332) with normoalbuminuria (n = 210), microalbuminuria (n = 83) and macroalbuminuria (n = 42) were enrolled. Creatinine, urinary albumin levels, serum/urine cystatin C and estimated glomerular filtration rate (eGFR by MDRD [Modification of Diet in Renal Disease] and CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] equations) were determined. The cystatin C levels of serum and urine increased with increasing degree of albuminuria, reaching higher levels in macroalbuminuric patients (P < 0.001). In multiple regression analysis, serum cystatin C was affected by C-reactive protein (CRP), sex, albumin-creatinine ratio (ACR) and eGFR. Urine cystatin C was affected by triglyceride, age, eGFR and ACR. In multivariate logistic analysis, cystatin C levels of serum and urine were identified as independent factors associated with eGFR < 60 mL/min/1.73 m2 estimated by MDRD equation in patients with normoalbuminuria. On the other hand, eGFR < 60 mL/min/1.73 m2 estimated by CKD-EPI equation was independently associated with low level of high-density lipoprotein in normoalbuminuric patients. The cystatin C levels of serum and urine could be useful markers for renal dysfunction in type 2 diabetic patients with normoalbuminuria.
doi:10.3346/jkms.2011.26.2.258
PMCID: PMC3031011  PMID: 21286018
Cystatin C; Diabetic Nephropathies; Albuminuria
22.  25-hydroxyvitamin D Levels and chronic kidney disease in the AusDiab (Australian Diabetes, Obesity and Lifestyle) study 
BMC Nephrology  2012;13:55.
Background
Low 25-hydroxy vitamin D (25(OH)D) levels have been associated with an increased risk of albuminuria, however an association with glomerular filtration rate (GFR) is not clear. We explored the relationship between 25(OH)D levels and prevalent chronic kidney disease (CKD), albuminuria and impaired GFR, in a national, population-based cohort of Australian adults (AusDiab Study).
Methods
10,732 adults ≥25 years of age participating in the baseline survey of the AusDiab study (1999–2000) were included. The GFR was estimated using an enzymatic creatinine assay and the CKD-EPI equation, with CKD defined as eGFR <60 ml/min/1.73 m2. Albuminuria was defined as a spot urine albumin to creatinine ratio (ACR) of ≥2.5 mg/mmol for men and ≥3.5 for women. Serum 25(OH)D levels of <50 nmol/L were considered vitamin D deficient. The associations between 25(OH)D level, albuminuria and impaired eGFR were estimated using multivariate regression models.
Results
30.7% of the study population had a 25(OH)D level <50 nmol/L (95% CI 25.6-35.8). 25(OH)D deficiency was significantly associated with an impaired eGFR in the univariate model (OR 1.52, 95% CI 1.07-2.17), but not in the multivariate model (OR 0.95, 95% CI 0.67-1.35). 25(OH)D deficiency was significantly associated with albuminuria in the univariate (OR 2.05, 95% CI 1.58-2.67) and multivariate models (OR 1.54, 95% CI 1.14-2.07).
Conclusions
Vitamin D deficiency is common in this population, and 25(OH)D levels of <50 nmol/L were independently associated with albuminuria, but not with impaired eGFR. These associations warrant further exploration in prospective and interventional studies.
doi:10.1186/1471-2369-13-55
PMCID: PMC3441805  PMID: 22759247
Albuminuria; Chronic kidney disease; Glomerular filtration rate; and Vitamin D
23.  Within-Person Variability in Kidney Measures 
Background
Our objective was to quantify the short-term total within-person variability in standard and nontraditional kidney measures using national data.
Study Design
Repeat examination study of serum and urine kidney measures.
Setting & Participants
Participants aged 18 or older in the Third National Health and Nutrition Examination Survey (NHANES III) who had repeat blood and urine samples collected during visits occurring ~18 days apart.
Measurements
Standardized serum creatinine, standardized cystatin C, β-trace protein (BTP), β2-microglobulin (B2M) and urine albumin and creatinine. We calculated the within-person coefficient of variation (CVw), which includes both biological and analytical variability. We also evaluated the impact of variability on estimates of the prevalence of reduced estimated glomerular filtration rate and albuminuria.
Results
Serum cystatin C demonstrated the lowest short-term within-person variability (CVw=6.8%). Serum creatinine and B2M (CVw values of 7.6% and 8.4%, respectively) also had low variability. BTP had the most variability of the serum markers (CVw=11.6%). As expected, urine albumin and urine creatinine concentration measurements exhibited high variability (CVw >30% for both), however the albumin-creatinine ratio performed much better than either measure alone, with a CVw of 11.3%. The effect of this variability on the prevalence of reduced estimated glomerular filtration rate was moderate, with an approximately 20% lower prevalence when defined based on single measurements compared to repeated application of the same test ~18 days apart. Repeat testing for albuminuria had a larger effect, showing a 33% lower prevalence of albuminuria when repeat testing was applied.
Limitations
Only two measurements available. General population with low prevalence of kidney disease.
Conclusions
Our results suggest that creatinine, cystatin C, and B2M have similarly low short-term variability. BTP was more variable compared to the other serum filtration makers. Urine albumin and creatinine were highly variable and may benefit from repeat assessments to reduce the misclassification of albuminuria.
doi:10.1053/j.ajkd.2012.11.048
PMCID: PMC3628297  PMID: 23337799
24.  Prevalence and prognosis of unrecognized myocardial infarctions in chronic kidney disease 
Nephrology Dialysis Transplantation  2011;27(9):3482-3488.
This study makes an important contribution by being one of the first to define the burden of clinically silent myocardial infarctions in the CKD community.
Background
Unrecognized myocardial infarctions (UMIs) are common in the general population but have not been well studied in patients with chronic kidney disease (CKD). The purpose of this study was to determine the prevalence and prognosis for mortality of UMI among adults with CKD.
Methods
The current study included 18 864 participants in the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study who completed a baseline examination including a 12-lead electrocardiogram (ECG). UMI was defined as the presence of myocardial infarction (MI) by Minnesota ECG classification in the absence of self-reported or recognized MI (RMI). Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation and albuminuria using albumin-to-creatinine ratio from a spot urine sample. All-cause mortality was assessed over a median 4 years of follow-up.
Results
The prevalence of UMI was 4, 6, 6 and 13% among participants with eGFR levels of ≥60, 45–59.9, 30–44.9 and <30 mL/min/1.73m2, respectively, and 4, 5, 7 and 10% among participants with albuminuria levels of <10, 10–29.9, 30–299.9 and ≥300 mg/g, respectively. Compared to those with no MI, the multivariable adjusted hazard ratio for all-cause mortality associated with UMI and RMI was 1.65 [95% confidence interval (CI): 1.09–2.49] and 1.65 (95% CI: 1.20–2.26), respectively, among individuals with an eGFR <60 mL/min/1.73m2 and 1.49 (95% CI: 1.03–2.16) and 1.88 (95% CI: 1.40–2.52) among individuals with albuminuria ≥30 mg/g.
Conclusion
UMIs are common among individuals with an eGFR <60 mL/min/1.73m2 and albuminuria and associated with an increased mortality risk.
doi:10.1093/ndt/gfr684
PMCID: PMC3433770  PMID: 22167594
chronic kidney disease; coronary artery disease; mortality
25.  Comparisons of creatinine and cystatin C for detection of kidney disease and prediction of all-cause mortality in HIV-infected women 
AIDS (London, England)  2013;27(14):2291-2299.
Background
Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine.
Design
Retrospective cohort analysis.
Methods
Cystatin C and creatinine were measured from specimens taken and stored during the 1999–2000 exam among 908 HIV-infected participants in the Women’s Interagency HIV study (WIHS). Mean follow-up was 10.2 years. The associations of baseline categories (<60, 60–90, and >90 mL/min/1.73m2) of creatinine eGFR (eGFRcr), cystatin C eGFR (eGFRcys), and combined creatinine-cystatin C eGFR (eGFRcr-cys) with all-cause mortality were evaluated using multivariable Cox regression. The net reclassification index (NRI) was calculated to evaluate the effect of cystatin C on reclassification of CKD staging.
Results
The prevalence of CKD (eGFR<60) at baseline was higher with eGFRcys (10.1%) compared to eGFRcr (6.7%, p=0.0006) and eGFRcr-cys (7.5%, p=0.011). Relative to eGFR >90, the eGFR <60 category by eGFRcys (Adjusted HR: 2.56; 95% CI: 1.63, 4.02), eGFRcr-cys (3.11; 1.94–5.00), and eGFRcr (2.34; 1.44–3.79) was associated with increased mortality risk. However, the eGFR 60–90 category was associated with increased mortality risk for eGFRcys (1.80; 1.28–2.53) and eGFRcr-cys (1.91; 1.38–2.66) but not eGFRcr (1.20; 0.85–1.67). The overall NRI for mortality was 26% when reclassifying from eGFRcr to eGFRcys (p<0.001) and was 20% when reclassifying from eGFRcr to eGFRcr-cys (p<0.001).
Conclusion
Cystatin C detected a higher prevalence of CKD relative to creatinine and improves CKD staging relative to creatinine by reclassifying individuals at the highest mortality risk to lower eGFR categories.
doi:10.1097/QAD.0b013e328362e874
PMCID: PMC3919542  PMID: 23669156
Creatinine; Cystatin C; Glomerular Filtration Rate; HIV; Mortality; Kidney; Women

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